Processes for producing polymer coatings for release of therapeutic agent

ABSTRACT

A method for furnishing a therapeutic-agent-containing medical device is provided. The method comprises: (a) providing a reactive layer comprising a cross-linking agent on a medical device surface; and (b) subsequently applying a polymer-containing layer, which comprises a polymer and a therapeutic agent, over the reactive layer. The cross-linking agent interacts with the polymer to form a cross-linked polymeric region that comprises the therapeutic agent. Examples of medical devices include implantable or insertable medical devices, for example, catheters, balloon, cerebral aneurysm filler coils, arterio-venous shunts and stents.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to medical devices with polymeric coatingsand more particularly to medical devices having polymer coatings thatrelease therapeutic agent.

2. Brief Description of the Background Art

Numerous medical devices have been developed for the delivery oftherapeutic agents to the body. For example, in accordance with somedelivery strategies, a therapeutic agent is provided within a polymericcarrier layer that is associated with a medical device. Once the medicaldevice is placed at the desired location within a patient, thetherapeutic agent is released from the medical device. The desiredrelease profile for the therapeutic agent is dependent upon theparticular treatment at hand, including the specific condition beingtreated/prevented, the specific therapeutic agent selected, the specificsite of administration, and so forth.

Therapeutic agents are frequently handled in aqueous solutions.Unfortunately, directly coating the surface of a metallic medicaldevice, for example, a stent, with an aqueous solution can beproblematic, because metals are typically quite hydrophobic. As aresult, the cohesive forces within the aqueous solution tend to pool thesolution on the medical device surface, rather than wetting the entiresurface. Low coating retention, frequently involving very expensivetherapeutic agents, is associated with this phenomenon.

SUMMARY OF THE INVENTION

The above and other issues are addressed by the present invention, inwhich a novel method is provided for producing a therapeutic agentreleasing medical device.

According one embodiment of the present invention, a reactive layercomprising a cross-linking agent is initially provided on a medicaldevice surface. Subsequently, a polymer-containing layer comprising apolymer and a therapeutic agent is applied over the reactive layer. Oncethe two layers have been established, the cross-linking agent from saidreactive layer is free to interact with the polymer in thepolymer-containing layer, forming a cross-linked polymeric region thatcontains the therapeutic agent.

Examples of medical devices include implantable or insertable medicaldevices, for example, catheters, balloons, cerebral aneurysm fillercoils, arterio-venous shunts and stents.

One advantage of the present invention is that a process is provided,which allows for the controlled manufacture of a therapeutic-containingpolymer layer on a medical device surface.

Another advantage of the present invention is that a process isprovided, which allows a hydrophobic medical device surface, such as ametallic surface, to be effectively wetted by an aqueous, or otherwisehydrophilic solution, containing a therapeutic agent, minimizing poolingor beading of the solution.

Still another advantage of the present invention is that a coating isprovided, which protects the therapeutic agent from rapid release duringmedical device deployment and also controls release of the therapeuticagent to the target location after deployment.

The above and other embodiments and advantages of the present inventionwill be readily understood by those of ordinary skill in the art uponreview of the Detailed Description and Claims to follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic perspective view illustrating astereo-lithographic deposition technique, in accordance with anembodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, a variety of methods aredescribed below for providing therapeutic-agent-releasing polymercoatings on medical device surfaces. These methods generally comprisethe following steps: (a) providing a medical device having on itssurface a reactive layer comprising a cross-linking agent; and (b)applying a polymer-containing layer, which comprises a polymer and atherapeutic agent, over the reactive layer. Once the polymer-containinglayer is applied, the cross-linking agent from the reactive layerinteracts with the polymer species from the polymer-containing layer toform a cross-linked polymeric region. The cross-linked polymeric regioncontains the therapeutic agent, and can be referred to as a matrix layeror a carrier layer.

Once formed, the cross-linked polymeric region typically (a) acts toretain therapeutic agent during device deployment and (b) releasestherapeutic agent in a controlled manner subsequent to devicedeployment. The use of in situ polymerization reduces the need to handlehighly viscous polymer solutions that contain therapeutic agents.

Preferred medical devices for use in conjunction with the presentinvention are implantable or insertable medical devices, includingcatheters (for example, urinary catheters or vascular catheters such asballoon catheters), guide wires, balloons, filters (e.g., vena cavafilters), stents (including coronary vascular stents, cerebral stents,urethral stents, ureteral stents, biliary stents, tracheal stents,gastrointestinal stents and esophageal stents), stent grafts, cerebralaneurysm filler coils (including GDC—Guglilmi detachable coils—and metalcoils), vascular grafts, myocardial plugs, patches, pacemakers andpacemaker leads, heart valves, and biopsy devices; indeed, any substrate(which can be, for example, metallic, polymeric or ceramic, preferablymetallic) which is coated in accordance with the present invention andwhich is designed for use in a patient, either for procedural use or asan implant.

The medical devices for use in connection with the present inventioninclude drug delivery medical devices for systemic treatment or fortreatment of any mammalian tissue or organ. As used herein, “treatment”refers the prevention of a disease or condition, the reduction orelimination of symptoms associated with a disease or condition, or thesubstantial or complete elimination a disease or condition. Preferredsubjects are mammalian subjects and more preferably human subjects.Non-limiting examples of tissues and organs for treatment include theheart, coronary or peripheral vascular system, lungs, trachea,esophagus, brain, liver, kidney, bladder, urethra and ureters, eye,intestines, stomach, colon, pancreas, ovary, prostate, gastrointestinaltract, biliary tract, urinary tract, skeletal muscle, smooth muscle,breast, cartilage and bone.

As previously indicated, in accordance with various embodiments of thepresent invention, a process is provided that comprises: (a) providing amedical device having on its surface a reactive layer that comprises across-linking agent; and (b) applying, over the reactive layer, apolymer-containing layer comprising (i) a polymer that is crosslinked bythe crosslinking agent and (ii) a therapeutic agent. After thepolymer-containing layer is established over the reactive layer, thecrosslinking agent and the polymer associate with one another, forexample, as a result of diffusion and/or any other mass-transportmechanism, leading to crosslinking of the polymer species. The reactivelayer and the polymer-containing layer are preferably sufficientlyreactive with one another to lead to crosslinking of essentially all ofthe polymer within the polymer-containing layer by the crosslinkingagent.

A “polymer” is any macromolecule composed of two or more monomers, andincludes dimers, trimers, tetramers, etc. A “monomer” is a polymerizablemolecule. Typically, the polymers of the present invention will have amedian number of monomers that numbers in the tens (10 to 99), hundreds(100 to 999), thousands (1000 to 9999), tens of thousands (10,000 to99,999) or more.

A “cross-linking agent” is any species that is capable of linking afirst polymer chain to a second polymer chain. Linking can be covalentor non-covalent (e.g., ionic). In some instances, at least a portion ofthe crosslinking agent becomes incorporated into the crosslinkedcomposition.

Crosslinkable polymers for use in connection with the present inventionmay be crosslinked using either non-ionic crosslinking (e.g., covalentcrosslinking) or ionic crosslinking.

Crosslinkable polymers suitable for the practice of the presentinvention include carboxylic, sulfate, hydroxy and amine-functionalizedpolymers, among others. Suitable crosslinkable polymers which may beused in the practice of the present invention include homopolymers,copolymers and polymer blends comprising one or more of the following:polyhydroxy ethyl methacrylate, polyvinyl alcohol, polyacrylamide, poly(N-vinyl pyrrolidone), polyethylene oxide, hydrolyzed polyacrylonitrile,polyacrylic acid, polymethacrylic acid, polyethylene amine, alginicacid, pectinic acid, carboxy methyl cellulose, hyaluronic acid, heparin,heparin sulfate, chitosan, carboxymethyl chitosan, chitin, pullulan,gellan, xanthan, carboxymethyl starch, carboxymethyl dextran,chondroitin sulfate, cationic guar, potassium polymetaphosphates (e.g.,Kurrol salts), cationic starch, as well as acid salts and esters thereofwhere appropriate.

Ionic crosslinking agents may be in the form of anions or cations,depending on whether the polymer to be crosslinked is cationically oranionically crosslinkable.

Appropriate cationic crosslinking agents include alkaline earth metals,such as calcium, magnesium, barium, strontium, and beryllium ions;transition metals, such as iron, manganese, copper, cobalt, zinc, andsilver ions; other metallic elements, such as boron, aluminum, lead, andbismuth ions; and polyamonium ions, such as ⁺H₃N(—H₂)_(n)—NH₃ ⁺ or⁺H₃N—(CH₂)_(n)—CH((CH₂)_(m)−NH₃ ⁺)((CH₂)_(p)—NH₃ ⁺) where n is aninteger ranging from 1 to 8, and m and p are integers ranging from 0 to8. Preferred cationic crosslinking agents are calcium and barium ions.

Anionic crosslinking agents appropriate for the practice of the presentinvention include those derived from polybasic organic or inorganicacids. Appropriate anionic crosslinking agents include phosphate,sulfate, citrate, borate, succinate, maleate, adipate, and oxalate ions.

One preferred embodiment of the present invention utilizes thefollowing: (a) a reactive layer comprising a multivalent cationiccrosslinking agent (e.g., calcium or barium) and (b) apolymer-containing layer comprising (i) one or more mono-valent salts ofalginic acid (e.g., sodium alginate and/or potassium alginate) and (ii)a therapeutic agent. In this embodiment, upon application of thepolymer-containing layer over the reactive layer, the divalent cationsfrom the reactive layer interact with the alginate polymers from thepolymer-containing layer, in the presence of the therapeutic agent,resulting in the formation of a cross-linked,therapeutic-agent-containing matrix.

Ionically crosslinked systems are particularly advantageous when used inconnection with medical devices having hydrophobic surfaces. This isbecause the salts that are typically used to provide the cationic oranionic crosslinking agent also act to reduce the surface tension of thesolution (generally aqueous) that is applied to the hydrophobic surface.As a result, coating retention is increased. Moreover, such salts aretypically inexpensive as compared to the therapeutic agent that is foundin the polymer-containing layer. By establishing a relativelyhydrophilic, salt-containing layer upon the device surface, retention ofthe subsequently applied polymer-containing layer, and hence retentionof therapeutic agent, is improved. Furthermore, such crosslinking agentsare frequently of low molecular weight, and hence of high mobility,enhancing interactions between the crosslinking agent and the polymer.

Preferred non-ionic crosslinking agents are those that react with groupspresent in the polymer such that covalent bonds are formed betweendifferent polymer chains. Suitable non-ionic crosslinking agents arepolyfunctional compounds having at least two functional groups reactivewith one or more functional groups present in the polymer(s). Exemplarycrosslinking agents contain one or more of the following: carboxygroups, hydroxy groups, epoxy groups, halogen groups amino functionalgroups, or hydrogen unsaturated groups, which are capable of undergoingfacile nucleophilic or condensation reactions with groups present in thepolymer at temperatures up to about 100° C. Suitable crosslinkingreagents include polycarboxylic acids or anhydrides; polyamines;epihalohydrins; diepoxides; dialdehydes (e.g., glutaraldehyde); diols;carboxylic acid halides, ketones and like compounds.

Other exemplary crosslinkable polymers for the practice of the presentinvention include polymers that contain amino acids (e.g., proteins),which can be covalently crosslinked to one another using an appropriatecrosslinking agent. For example, the polymer-containing layer cancomprise either (a) a polymer containing both lysine and glutamine or(b) a polymer containing lysine and a polymer containing glutamine. Acorresponding crosslinking agent appropriate for use in this reactivelayer is a transglutaminase enzyme. Upon application of thepolymer-containing layer to the reactive layer, the transglutaminaseenzyme from the reactive layer acts to covalently bond the glutamine andlysine within the polymer(s) in the presence of the therapeutic agent,forming a cross-linked therapeutic-agent-containing matrix.

The reactive layer can be applied on the medical device surface by anyappropriate method. Preferred techniques include casting, spin coating,web coating, stereo-lithographic deposition, spraying, dipping, coatingvia air suspension and mechanical suspension techniques, positivedisplacement coating techniques, ink jet techniques, electrostatictechniques, and combinations of these processes. Spraying is afrequently used technique where coating retention is not of greatconcern (e.g., where the cost of the materials present in thecrosslinking agent are relatively low).

The polymer-containing layer is subsequently deposited over the reactivelayer. Preferably the cross-linkable polymer and the therapeutic agentare dissolved or dispersed in a carrier liquid, for example, water or anorganic liquid. Because therapeutic agents are commonly handled inaqueous solutions, water is commonly preferred.

The polymer-containing layer can be applied over the reactive layer byany appropriate method, include the techniques set forth above. Aspreviously noted, therapeutic agents are, in general, quite expensive.Hence, it is typically desirable to use techniques having high coatingretention, of which stereo-lithographic deposition is one example.

Stereo-lithographic deposition (SLD) is a process by which material canbe applied onto a surface to obtain a 3-dimentional structure. Thisstructure can be created through repetitive layering of the coatingmaterial. In the case of small medical devices, such as endoluminalstents, SLD can provide the means for building a therapeutic coating ina specific location.

Referring now to FIG. 1, for example, a stent element 12 is illustrated,to which a reactive layer (not separately illustrated) has previouslybeen applied. A nozzle 14 dispenses the polymer-containing layer 16 overthe stent element 12, precisely directing the deposition location of thepolymer-containing layer 16. After deposition, the polymer within thepolymer-containing layer 16 reacts with the crosslinking agent that ispresent on the surface to form therapeutic-agent-containing crosslinkedpolymer network. Upon drying, the crosslinked network is securelyattached to the stent surface. The resulting crosslinked network ispreferably sufficiently durable to withstand stent crimping andexpansion.

One illustrative analog of SLD would be writing on a radiator grill witha tube of toothpaste. The nozzle of the toothpaste tube allows one tocontrol the lay of the bead of toothpaste. Pressure on the tube and thedistance of the nozzle from the grill surface can control the thicknessof the bead. Sometimes, the viscosity of the SLD coating material ishigh enough to facilitate such a toothpaste analogy. However, this isnot always the case. Nonetheless, in the event that a low viscositypolymer-containing layer is deposited using the SLD process, the processof the present invention will render the polymer-containing layer moreviscous upon contacting the surface due to the crosslinking thatsubsequently occurs, improving coating retention.

Moreover, as indicated above, the reactive layer generally presents arelatively hydrophilic surface for the subsequently appliedpolymer-containing layer. Where an aqueous-based liquid is applied tocreate the polymer-containing layer, the presence of this hydrophilicsurface further improves coating retention and uniformity.

Of course, other techniques other than SLD can be used to create thepolymer-containing layer. One preferred technique, particularly wherehigh coating retention is not required, is spray coating. As with SLD,coating thickness can be varied, for example, by modification of coatingprocess parameters, including increasing spray flow rate, slowingmovement between the substrate to be coated and the spray nozzle,providing repeated passes, and so forth.

“Therapeutic agents”, “pharmaceutically active agents”,“pharmaceutically active materials”, “drugs” and other related terms maybe used interchangeably herein and include genetic therapeutic agents,non-genetic therapeutic agents and cells.

Exemplary non-genetic therapeutic agents for the practice of theinvention include: (a) anti-thrombotic agents such as heparin, heparinderivatives, urokinase, and PPack (dextrophenylalanine proline argininechloromethylketone); (b) anti-inflammatory agents such as dexamethasone,prednisolone, corticosterone, budesonide, estrogen, sulfasalazine andmesalamine; (c) antineoplastic/antiproliferative/anti-mitotic agentssuch as paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,epothilones, endostatin, angiostatin, angiopeptin, monoclonal antibodiescapable of blocking smooth muscle cell proliferation, and thymidinekinase inhibitors; (d) anesthetic agents such as lidocaine, bupivacaineand ropivacaine; (e) anti-coagulants such as D-Phe-Pro-Arg chloromethylketone, an RGD peptide-containing compound, heparin, hirudin,antithrombin compounds, platelet receptor antagonists, anti-thrombinantibodies, anti-platelet receptor antibodies, aspirin, prostaglandininhibitors, platelet inhibitors and tick antiplatelet peptides; (f)vascular cell growth promoters such as growth factors, transcriptionalactivators, and translational promotors; (g) vascular cell growthinhibitors such as growth factor inhibitors, growth factor receptorantagonists, transcriptional repressors, translational repressors,replication inhibitors, inhibitory antibodies, antibodies directedagainst growth factors, bifunctional molecules consisting of a growthfactor and a cytotoxin, bifunctional molecules consisting of an antibodyand a cytotoxin; (h) protein kinase and tyrosine kinase inhibitors(e.g., tyrphostins, genistein, quinoxalines); (i) prostacyclin analogs;(j) cholesterol-lowering agents; (k) angiopoietins; (l) antimicrobialagents such as triclosan, cephalosporins, aminoglycosides andnitrofurantoin; (m) cytotoxic agents, cytostatic agents and cellproliferation affectors; (n) vasodilating agents; and (o)agents thatinterfere with endogenous vasoactive mechanisms.

Exemplary genetic therapeutic agents for the practice of the inventioninclude anti-sense DNA and RNA as well as DNA coding for: (a) anti-senseRNA, (b) tRNA or rRNA to replace defective or deficient endogenousmolecules, (c) angiogenic factors including growth factors such asacidic and basic fibroblast growth factors, vascular endothelial growthfactor, epidermal growth factor, transforming growth factor α and β,platelet-derived endothelial growth factor, platelet-derived growthfactor, tumor necrosis factor α, hepatocyte growth factor andinsulin-like growth factor, (d) cell cycle inhibitors including CDinhibitors, and (e) thymidine kinase (“TK”) and other agents useful forinterfering with cell proliferation. Also of interest is DNA encodingfor the family of bone morphogenic proteins (“BMP's”), including BMP-2,BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10,BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Currently preferredBMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. Thesedimeric proteins can be provided as homodimers, heterodimers, orcombinations thereof, alone or together with other molecules.Alternatively, or in addition, molecules capable of inducing an upstreamor downstream effect of a BMP can be provided. Such molecules includeany of the “hedgehog” proteins, or the DNA's encoding them.

Some additional exemplary genetic therapeutic agents for the practice ofthe invention include DNA encoding for the following: cytokines such ascolony stimulating factors (e.g., granulocyte-macrophagecolony-stimulating factor), tumor necrosis factors (e.g., fas ligand)and interleukins (e.g., IL-10, an anti-inflammatory interleukin), aswell as protease inhibitors, particularly serine protease inhibitors(e.g., SERP-1), tissue inhibiting metalloproteinases (e.g., TIMP-1,TIMP-2, TIMP-3, TIMP-4), monocyte chemoattractant proteins (e.g.,MCP-1), protein kinase inhibitors including cyclin-dependent kinaseinhibitors (e.g., p27, p21), endogenous and inducible nitric oxidesynthase, CO-generating enzymes, such as hemoxygenases, which catalyzethe oxidation of heme into the biologically active molecules ironbiliverdin and CO (e.g., HOI-1), antiproliferative compounds, such ashKIS in a transdominant mutant peptide form, which are capable ofinterfering with the ability of endogenous hKIS to phosphorylate p27thereby enhancing cell cycle arrest, as well as derivatives of theforegoing.

Vectors for delivery of genetic therapeutic agents include viral vectorssuch as adenoviruses, gutted adenoviruses, adeno-associated virus,retroviruses, alpha virus (Semliki Forest, Sindbis, etc.), lentiviruses,herpes simplex virus, replication competent viruses (e.g., ONYX-015) andhybrid vectors; and non-viral vectors such as artificial chromosomes andmini-chromosomes, plasmid DNA vectors (e.g., pCOR), cationic polymers(e.g., polyethyleneimine, polyethyleneimine (PEI)), graft copolymers(e.g., polyether-PEI and polyethylene oxide-PEI), neutral polymers PVP,SP1017 (SUPRATEK), lipids such as cationic lipids, liposomes,lipoplexes, nanoparticles, or microparticles, with and without targetingsequences such as the protein transduction domain (PTD), as well asother transfection enhancing agents.

Cells include cells of human origin (autologous or allogeneic),including stem cells, or from an animal source (xenogeneic), which canbe genetically engineered if desired to deliver proteins of interest.

Numerous therapeutic agents, not necessarily exclusive of those listedabove, have been identified as candidates for vascular treatmentregimens, for example, as agents targeting restenosis. Such agents areappropriate for the practice of the present invention and include one ormore of the following: (a) Ca-channel blockers includingbenzothiazapines such as diltiazem and clentiazem, dihydropyridines suchas nifedipine, amlodipine and nicardapine, and phenylalkylamines such asverapamil, (b) serotonin pathway modulators including: 5-HT antagonistssuch as ketanserin and naftidrofuryl, as well as 5-HT uptake inhibitorssuch as fluoxetine, (c) cyclic nucleotide pathway agents includingphosphodiesterase inhibitors such as cilostazole and dipyridamole,adenylate/guanylate cyclase stimulants such as forskolin, as well asadenosine analogs, (d) catecholamine modulators including α-antagonistssuch as prazosin and bunazosine, β-antagonists such as propranolol andα/β-antagonists such as labetalol and carvedilol, (e) endothelinreceptor antagonists, (f) nitric oxide donors/releasing moleculesincluding organic nitrates/nitrites such as nitroglycerin, isosorbidedinitrate and amyl nitrite, inorganic nitroso compounds such as sodiumnitroprusside, sydnonimines such as molsidomine and linsidomine,nonoates such as diazenium diolates and NO adducts of alkanediamines,S-nitroso compounds including low molecular weight compounds (e.g.,S-nitroso derivatives of captopril, glutathione and N-acetylpenicillamine) and high molecular weight compounds (e.g., S-nitrosoderivatives of proteins, peptides, oligosaccharides, polysaccharides,synthetic polymers/oligomers and natural polymers/oligomers), as well asC-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds andL-arginine, (g) ACE inhibitors such as cilazapril, fosinopril andenalapril, (h) ATII-receptor antagonists such as saralasin and losartin,(i) platelet adhesion inhibitors such as albumin and polyethylene oxide,(j) platelet aggregation inhibitors including aspirin and thienopyridine(ticlopidine, clopidogrel) and GP IIb/IIIa inhibitors such as abciximab,epitifibatide and tirofiban, (k) coagulation pathway modulatorsincluding heparinoids such as heparin, low molecular weight heparin,dextran sulfate and β-cyclodextrin tetradecasulfate, thrombin inhibitorssuch as hirudin, hirulog, PPACK(D-phe-L-propyl-L-arg-chloromethylketone)and argatroban, FXa inhibitors such as antistatin and TAP (tickanticoagulant peptide), Vitamin K inhibitors such as warfarin, as wellas activated protein C, (l) cyclooxygenase pathway inhibitors such asaspirin, ibuprofen, flurbiprofen, indomethacin and sulfinpyrazone, (m)natural and synthetic corticosteroids such as dexamethasone,prednisolone, methprednisolone and hydrocortisone, (n) lipoxygenasepathway inhibitors such as nordihydroguairetic acid and caffeic acid,(o) leukotriene receptor antagonists, (p) antagonists of E- andP-selectins, (q) inhibitors of VCAM-1 and ICAM-1 interactions, (r)prostaglandins and analogs thereof including prostaglandins such as PGE1and PGI2 and prostacyclin analogs such as ciprostene, epoprostenol,carbacyclin, iloprost and beraprost, (s) macrophage activationpreventers including bisphosphonates, (t) IIMG-CoA reductase inhibitorssuch as lovastatin, pravastatin, fluvastatin, simvastatin andcerivastatin, (u) fish oils and omega-3-fatty acids, (v) free-radicalscavengers/antioxidants such as probucol, vitamins C and E, ebselen,trans-retinoic acid and SOD mimics, (w) agents affecting various growthfactors including FGF pathway agents such as bFGF antibodies andchimeric fusion proteins, PDGF receptor antagonists such as trapidil,IGF pathway agents including somatostatin analogs such as angiopeptinand ocreotide, TGF-β pathway agents such as polyanionic agents (heparin,fucoidin), decorin, and TGF-β antibodies, EGF pathway agents such as EGFantibodies, receptor antagonists and chimeric fusion proteins, TNF-αpathway agents such as thalidomide and analogs thereof, Thromboxane A2(TXA2) pathway modulators such as sulotroban, vapiprost, dazoxiben andridogrel, as well as protein tyrosine kinase inhibitors such astyrphostin, genistein and quinoxaline derivatives, (x) MMP pathwayinhibitors such as marimastat, ilomastat and metastat, (y) cell motilityinhibitors such as cytochalasin B, (z) antiproliferative/antineoplasticagents including antimetabolites such as purine analogs (e.g.,6-mercaptopurine or cladribine, which is a chlorinated purine nucleosideanalog), pyrimidine analogs (e.g., cytarabine and 5-fluorouracil) andmethotrexate, nitrogen mustards, alkyl sulfonates, ethylenimines,antibiotics (e.g., daunorubicin, doxorubicin), nitrosoureas, cisplatin,agents affecting microtubule dynamics (e.g., vinblastine, vincristine,colchicine, paclitaxel and epothilone), caspase activators, proteasomeinhibitors, angiogenesis inhibitors (e.g., endostatin, angiostatin andsqualamine), rapamycin, cerivastatin, flavopiridol and suramin, (aa)matrix deposition/organization pathway inhibitors such as halofuginoneor other quinazolinone derivatives and tranilast, (bb)endothelialization facilitators such as VEGF and RGD peptide, (cc) bloodrheology modulators such as pentoxifylline, and (dd) endothelial-cellspecific mitogens.

Several of the above and numerous additional therapeutic agentsappropriate for the practice of the present invention are also disclosedin U.S. Pat. No. 5,733,925 assigned to NeoRx Corporation, the entiredisclosure of which is incorporated by reference.

Therapeutic agents may be used singly or in combination.

A wide range of therapeutic agent loadings can be used in connectionwith the above polymeric coatings, with the amount of loading beingreadily determined by those of ordinary skill in the art and ultimatelydepending upon the condition to be treated, the nature of thetherapeutic agent itself, the avenue by which thetherapeutic-agent-loaded polymeric coating is administered to theintended subject, and so forth. The loaded polymeric coating willfrequently comprise from 1% or less to 70 wt % or more therapeuticagent.

EXAMPLE

In this example, a cross-linking agent is applied to the surface of astent. The therapeutic is then delivered to the stent surface within apolymer solution. When the polymer solution contacts the cross-linkingagent on the surface of the stent, the polymer forms a gel, and thetherapeutic is held in a crosslinked matrix on the surface of the stent.

The following materials are used: (a) 2.5% (w/w) sodium alginate polymersolution (aqueous), (b) 1.0% (w/w) calcium chloride solution (aqueous),(c) Boston Scientific Express™ 8 mm coronary stent, Boston Scientific,Natick Mass., USA, (d) 26 gauge hypodermic needle w/syringe, (e)stereoscopic light microscope, (f) stent spray coater, and (g)Teflon-coated mandrels.

Stents are initially spray coated with the CaCl₂ solution and allowed todry for 3 hours at 37° C. Sodium Alginate solution is then loaded intohypodermic syringe using care to eliminate any bubbles in the syringe.Dried stents are loaded onto mandrels, and using the light microscope,the needle tip is moved into a position directly over a CaCl₂-coatedstent strut. Gentle pressure is used to introduce the alginate solutionfrom the needle to the stent surface. With reference to FIG. 1, and toassist in visualizing the procedure, the stent strut can be thought ofas corresponding to numeral 12, the needle to numeral 14, and thealginate solution to numeral 16.

Subsequent to application of the alginate on the CaCl₂-coated stentsurface, the sodium alginate, which is a yellowish color, turns anoticeable shade of green. There appears to be some volume loss(shrinking) of the alginate as it gels as well. Alginate gels anywherethat CaCl₂ is present, but it does not do so on bare metal. Scratchingthe surface with a needle after depositing the alginate reveals agel-like substance. Prolonged exposure to the microscope lights appearsto dry the alginate gel and create a crystalline surface.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

1. A method for providing a therapeutic-agent-containing medical device,said method comprising: (a) providing a reactive layer comprising across-linking agent on a medical device surface; and (b) applying apolymer-containing layer comprising a polymer and a therapeutic agentover said reactive layer by stereo-lithographic deposition, wherein saidcross-linking agent interacts with said polymer to form a cross-linkedpolymeric region comprising said therapeutic agent.
 2. The method ofclaim 1, wherein said medical device is an implantable or insertablemedical device.
 3. The method of claim 1, wherein said medical device isselected from a catheter, a balloon, a cerebral aneurysm filler coil andan arterio-venous shunt.
 4. The method of claim 1, wherein said medicaldevice is a stent.
 5. The method of claim 4, wherein said device is avascular stent.
 6. The method of claim 1, wherein said crosslinkingagent is an ionic crosslinking agent.
 7. The method of claim 6, whereinsaid crosslinking agent is a cationic crosslinking agent.
 8. The methodof claim 7, wherein said polymer is a mono-valentpoly-glycosamino-glycan polymer.
 9. The method of claim 8, wherein saidpolymer is sodium alginate.
 10. The method of claim 8, wherein saidcrosslinking agent comprises calcium cations.
 11. The method of claim 1,wherein said crosslinking agent is a covalent crosslinking agent. 12.The method of claim 11, wherein said covalent crosslinking agentcovalently bonds two amino acids.
 13. The method of claim 1, whereinsaid polymer-containing layer further comprises water at the time ofapplication.
 14. The method of claim 1, wherein said therapeutic agentcomprises protein.
 15. The method of claim 1, wherein said therapeuticagent comprises whole cells.
 16. The method of claim 15, wherein saidtherapeutic agent further comprises extracellular matrix components. 17.The method of claim 1, wherein said therapeutic agent comprises DNA. 18.The method of claim 17, wherein said therapeutic agent further comprisesa vector for delivering said DNA.
 19. The method of claim 18, whereinsaid vector is a viral vector.
 20. The method of claim 1, wherein saidmedical device surface is a hydrophobic surface, wherein said reactivelayer is provided on said hydrophobic surface in the form of an aqueousliquid comprising water and said cross-linking agent, and wherein saidpolymer-containing layer is applied on said reactive layer in the forman aqueous liquid comprising a polymer, a therapeutic agent and water.21. The method of claim 1, wherein said medical device surface is ametallic surface, wherein said reactive layer is provided on saidmetallic surface in the form of an aqueous liquid comprising water andan ionic cross-linking agent, and wherein said polymer-containing layeris applied on said reactive layer in the form an aqueous liquidcomprising an ionically cross-linkable polymer, a therapeutic agent andwater.
 22. The method of claim 1, wherein said medical device surface isa metallic surface, wherein said reactive layer is provided on saidmetallic surface in the form of an aqueous liquid comprising water and acationic cross-linking agent, and wherein said polymer-containing layeris applied on said reactive layer in the form an aqueous liquidcomprising a cationically cross-linkable polymer, a therapeutic agentand water.
 23. The method of claim 1, wherein the reactive layerprovided prior to the application of the polymer-containing layer doesnot comprise a therapeutic agent.
 24. The method of claim 1, wherein thereactive layer and the polymer-containing layer are sufficientlyreactive with one another such that essentially all of the polymerwithin the polymer-containing layer is crosslinked by the crosslinkingagent.
 25. A method for providing a therapeutic-agent-containing medicaldevice, said method comprising: (a) providing a reactive layercomprising a transglutaminase crosslinking agent on a medical devicesurface; and (b) applying a polymer-containing layer comprising apolymer and a therapeutic agent over said reactive layer, wherein saidcross-linking agent interacts with said polymer to form a cross-linkedpolymeric region comprising said therapeutic agent.
 26. The method ofclaim 25, wherein said polymer-containing layer is applied by spraycoating.